Collaborative Research: MODULUS: Copy Number Alterations and Xenobiotic adaptation

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Understanding evolution is fundamental to understanding life on earth. Evolution also creates some of the greatest challenges to human health. Viruses, bacteria, fungi, and cancer cells all evolve resistance to xenobiotics. These xenobiotics are molecules that are not found naturally but that influence evolution in the natural world. This project aims to create new theory and experiments to understand xenobiotic evolution. The results of this project would have applications across many different fields such as bacteria resistant to antibiotics, malaria parasites resistant to antimalarial drugs, tumor cells resistant to cancer drugs, plants resistant to herbicides, and insects resistant to insecticides. The award provides support to train STEM graduate students that will eventually become part of the workforce. The project also provides research opportunities for undergraduates and develops new educational games that teach K-12 students about science, using xenobiotic evolution as an example.The main goal of this project is to discover novel aspects of xenobiotic adaptation that result from the interactions between mutations and gene amplifications. The project examines the complex, nonlinear evolutionary pathways that lead to xenobiotic adaptation in the context of antibiotic resistance evolution induced by Rifampin in E. coli. Mathematically, the project would model resistance evolution as a function of plasmid copy number with the use of a stochastic process that accounts for tunneling rates and spatial structures of the community of evolving cells. The project makes use of an incoherent feed forward loop that gives synthetic control for providing variation in plasmid copy numbers in cells while keeping biochemical levels constant. Synthetic biology experiments are designed with a view to parametrizing the models under development and exploring the effects of specific parameters that have been indicated as important by the model.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.